KR20200036920A - How to treat behavioral changes - Google Patents

Abstract

The present invention is a KDM1A inhibitor, especially 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole-2-amine It provides a way to treat behavioral changes.

Description

How to treat behavioral changes

The present invention relates to a method of treating behavioral changes.

For example, behavioral changes, such as social withdrawal or aggressive behavior, are very common in society today and are themselves regarded by clinicians as medical conditions. Still, the treatment of behavioral changes remains a medical challenge. There are currently no approved drugs specifically targeted for the treatment of social atrophy, aggressive behavior or other behavioral changes. In addition, existing drugs that have been used to treat behavioral changes can cause serious side effects; For example, many antipsychotics (also called nerve relaxants or major neurostabilizers) that have been used to treat aggressive behavior and other behavioral changes are sedation.

Thus, new and / or improved drugs to treat behavioral changes, particularly those that act through new mechanisms allowed to treat behavioral changes and / or exhibit a more favorable side effect profile than current treatments, There is an unmet need. The present invention addresses these and other needs.

The present invention provides a novel method of treating behavioral changes using KDM1A inhibitors.

Accordingly, the present invention provides a KDM1A inhibitor for use in the treatment of behavioral changes.

The present invention also provides a method of treating behavioral changes in a patient (especially a human) comprising administering a therapeutically effective amount of a KDM1A inhibitor to the patient.

The present invention also provides the use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of behavioral changes.

The present invention also provides the use of a KDM1A inhibitor for the treatment of behavioral changes.

In some embodiments, the behavior change is a social behavior change. In some embodiments, the behavior change is aggression or social atrophy.

In a preferred embodiment, the KDM1A inhibitor is 5-((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole-2- Amines, or pharmaceutically acceptable salts or solvates thereof.

1 is a KDM1A inhibitor compound 1 (as defined below and in Example 1) for aggressive behavior, as assessed by the total number of attacks, in a resident invasion test of male SAMP8 mice, as described in more detail in Example 3. (As shown). Mean and standard error of the mean (SEM) are shown. * p <0.05; ** p <0.01.
FIG. 2 shows the effect of treatment of compound 1 on aggressive behavior, as assessed by clinch attack number, in a resident invasion test of male SAMP8 mice, as described in more detail in Example 3. Mean and standard error of the mean (SEM) are shown. ** p <0.01; *** p <0.001.
FIG. 3 is compound 1 for social avoidance, as assessed by time without social interaction (measured in seconds), in a resident invader test in an isolated rat model, as described in more detail in Example 4. It shows the effect of treatment. Mean and standard error of the mean (SEM) are shown. * p <0.05; ** p <0.01.
FIG. 4 shows the effect of treatment of Compound 1 on social avoidance, as assessed by the number of avoidances, in a resident invader test in an isolated rat model, as described in more detail in Example 4. Mean and standard error of the mean (SEM) are shown. * p <0.05; *** p <0.001.
FIG. 5 is a social interaction behavior in a three-chamber test (TCT), as assessed by time spent in each of the observation and mouse chambers (measured in seconds), as described in more detail in Example 5. It shows the effect of compound 1 on. Mean and standard error of the mean (SEM) are shown. *** p <0.001.
FIG. 6 shows the effect of compound 1 on social interaction behavior in TCT, as assessed by the time spent exploring new mice directly, as described in more detail in Example 5. Mean and standard error of the mean (SEM) are shown. *** p <0.001.

The present invention is based on the discovery that KDM1A inhibitors are useful as therapeutic agents for the treatment of behavioral changes, described in more detail below, and described in the Examples.

Accordingly, the present invention provides a KDM1A inhibitor for use in the treatment of behavioral changes.

The present invention also provides a method of treating behavioral changes in a patient (especially a human) comprising administering a therapeutically effective amount of a KDM1A inhibitor to a patient.

The present invention also provides the use of a KDM1A inhibitor to prepare a medicament for the treatment of behavioral changes.

The present invention also provides the use of a KDM1A inhibitor for the treatment of behavioral changes.

According to the present invention, “behavior alteration”, in particular, affects alteration, disturbance, dysfunction, aberration, disorder or behavior of an individual. One, but not limited to, behavioral changes induced or related by genetic or acquired mutations, disease-related behavioral changes, drug-induced behavioral changes, acute and / or chronic drug abuse Behavioral changes, or behavioral changes induced by adverse social circumstances (eg, abandonment or neglect in childhood, traumatic experiences such as war or sexual assault in adulthood).

Behavioral changes according to the invention do not include changes in cognitive function (eg, memory impairment) or mood (eg, depression).

In some embodiments, the behavior change is a social behavior change. In particular, social behavioral changes are, but are not limited to, changes, disturbances, dysfunction, deviations, disabilities or social behavior of the individual, social behavioral changes induced by, for example, genetic or acquired mutations (e.g. For example, social interaction changes or aggression), disease-related social behavior changes (eg, social interaction changes or aggression), and drug-induced social behavior changes (eg, social interaction changes or aggression). , Social behavioral changes (e.g., social interaction changes or aggression) induced by the abuse of acute and / or chronic drugs, or adverse social conditions (e.g., childhood abandonment or neglect, traumatic experiences such as war, or Sexual assault in adulthood). Examples of social behavior changes according to the present invention include, but are not limited to, social atrophy, aggression, or numbness.

Accordingly, the present invention also provides a KDM1A inhibitor for use in the treatment of behavior disorder, behavioral dysfunction, behavioral deviation, or behavioral disorder, particularly social behavioral disturbance, social behavioral dysfunction, social behavioral deviation, or social behavioral disorder. It is about. Similarly, the present invention also provides a method of treating behavioral disturbance, behavioral dysfunction, behavioral deviation, or behavioral disorder (especially social behavioral disturbance, social behavioral dysfunction, social behavioral deviation, or social behavioral disorder) in a patient (especially a human). Provided, the method comprises administering to the patient a therapeutically effective amount of a KDM1A inhibitor. Social behavioral disturbances, social behavioral dysfunctions, social behavior deviations, or social behavioral disorders can be, in particular, social atrophy, aggression, or numbness. In addition, any of the conditions mentioned above may, for example, be (i) induced or related by genetic or acquired mutations, (ii) related to disease, and (iii) induced by drug treatment. And (iv) can be induced by abuse of acute and / or chronic drugs, or (v) by an adverse social environment as described in more detail below.

"Social withdrawal" in accordance with the present invention is particularly suitable for members of social species, such as humans, an abnormal lack of abnormal, pathological or social interaction and / or a reduced degree of social interaction (including social avoidance), Particularly when there are others, the individual consistently (over the course of time and time) expresses dogmatic behavior, often associated with a phenomenon of disassociation between society and individuals accompanied by indifference or exclusion. In this regard, social atrophy (also referred to as passive atrophy) appears to be caused by an internal factor that an individual chooses not to interact with others for any reason. The social atrophy according to the present invention is the active social isolation used to indicate the lack of social interaction due to external factors, for example, the process whereby an individual stays alone because colleagues do not want to communicate with him / her. It does not include (i.e., the individual is quarantined by others). Non-limiting examples of social atrophy to be treated in accordance with the present invention include social atrophy, disease (e.g., autism categorical disorder (ASD, e.g. For example, autism or Aspergus syndrome, evasive personality disorder (AvPD), schizophrenia (including, for example, schizotypal and / or delusional disorder), mood disorder (eg, major depressive disorder; mood-depressive disorder; or Bipolar disorder), drug addiction, post-traumatic stress disorder (PTSD), dementia (for example, Alzheimer's disease), paranoid personality disorder, depressive personality disorder, schizoaffective disorder, traumatic brain injury (TBI), or eating Social atrophy associated with a disability (e.g., including bulimia nervosa), social atrophy induced by drug therapy, social atrophy induced by abuse of acute and / or chronic drugs (e.g., including dependent syndrome), or Adverse social And social atrophy induced by the environment (eg, abandonment or neglect in childhood, traumatic experiences such as war or sexual assault in adulthood).

"Aggressiveness" according to the present invention, in particular, for example, physical or verbal interpersonal aggression (ie, towards another object), and / or intrapersonal aggression (ie, self-aggression). Any kind of abnormal, pathological or inappropriate aggressive or violent behavior, hostility or agitation, including. Non-limiting examples of aggressiveness to be treated in accordance with the present invention are, but are not limited to, genetic or acquired mutations (e.g. Trisomy 21, GABRA2, MAOA, SLC6A4, CHMP2B, VPS13A, PLA2G6, TBP, HTT, ANK3, EHMT1, MYCN, CASK, HDAC4, MLL / KMT2A, TCF4, CNTNAP2, NRXN1, ATN1, CTNNB1, MED12, KDM5C / JARID1C, CUL4B, SYN1, UBE2A, SMARCA2, HCFC1, HERC2, NDP13, PAK3 Aggression, disease (e.g., Alzheimer's disease (AD), Huntington's disease (HD), Lewy body dementia (DLB), Parkinson's disease (PD)) induced or related by STAMBP, HPRT1, DJ1, TARDBP, MAPT or AVPR1A) Schizophrenia (SZ), bipolar disorder (BPD), depression (DS), traumatic brain injury (TBI), REM sleep behavior disorder (RBD), dementia, dendritic nuclear biliary tract hypothalamic atrophy (DRPLA), Tourette syndrome (GTS) , Aggression, drug addiction, and stress related quality associated with behavioral disorders (including, for example, unsocialized behavioral disorders, socialized behavioral disorders, or hostile rebellious disorders) (Including, for example, post-traumatic stress disorder), autism categorical disorder (ASD), borderline personality disorder, or adult attention deficit hyperactivity disorder), aggressiveness, toxins (e.g., trimethyl) induced by drug therapy Aggression induced by acute and / or chronic drug abuse (e.g., including atrophy), aggression induced by dietary deficit (e.g., Zn), sleep Aggression induced by a tribe, or aggression induced by an adverse social environment (eg, abandonment or neglect in childhood, traumatic experiences such as war or sexual assault in adulthood).

In the context of disease-related social atrophy or disease-related aggression, diseases listed as examples of diseases are likewise examples of disease not only in the context of disease-related behavioral changes, but also in the context of disease-related social behavioral changes.

In some embodiments, behavioral changes are social atrophy.

In some embodiments, the behavioral change is social atrophy associated with the disease. In some embodiments, the disease is a CNS disease. In some embodiments, the CNS disease is autism spectrum disorder (e.g., ASD such as autism or Asperger's syndrome), avoidant personality disorder (AVPD), schizophrenia (split and / or Or delusional disorders), mood disorders (eg major depressive disorder, mood disorders; or bipolar disorder), drug addiction, post-traumatic stress disorder (PTSD), dementia (eg Alzheimer's disease) ), Paranoid personality disorder, depressive personality disorder, schizophaffective disorder, TBI, or eating disorders (including, for example, bulimia nervosa).

In some embodiments, the behavior change is aggressive.

In some embodiments, the behavioral change is disease-related aggression. In some embodiments, the disease is a CNS disease. In some embodiments, the CNS disease is AD, HD, DLB, PD, SZ, BPD, DS, TBI, RBD, dementia, DRPLA, GTS, behavioral disorder (e.g., non-socialized behavioral disorder, socialized behavioral disorder) , Or hostile rebellious disorder), drug addiction, stress-related disorders (eg including post-traumatic stress disorder), ASD, borderline personality disorder, or adult attention deficit hyperactivity disorder. In a preferred embodiment, the disease is AD. However, the disease may be different from AD. For example, the disease may be HD, DLB, PD, SZ, BPD, DS, TBI, RBD, dementia, DRPLA, GTS, behavioral disorders (e.g., non-narcissistic behavioral disorder, socialized behavioral disorder, or hostile) Rebellious disorder), drug addiction, stress-related diseases (including post-traumatic stress disorder), ASD, borderline personality disorder, or adult attention deficit hyperactivity disorder.

In some embodiments, the behavior change is apathy.

In the treatment methods and therapeutic uses described herein, any KDM1A inhibitor may be used, including KDM1A inhibitors as described in more detail below herein. However, KDM1A inhibitors for use in the methods and uses of the present invention are compounds 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3, 4-Oxadiazole-2-amines, or pharmaceutically acceptable salts or soluble compounds thereof are preferred, and in particular the KDM1A inhibitor is compound 5-(((((1R, 2S) -2- (4- (benzyloxy) ) Phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole-2-amine (non-salt form) is preferred. This compound is also referred to herein as Compound 1 or Comp. It is designated as 1. Name "5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole-2-amine", "Compound 1 (Compound 1) "or" Comp. 1 "are used interchangeably herein.

Thus, the present invention is 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxa for use in the treatment of behavioral changes. Diazol-2-amine, or a pharmaceutically acceptable salt or soluble compound thereof.

The present invention also provides a therapeutically effective amount of 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole to a patient. It is to provide a method for treating behavioral changes in patients (especially humans) comprising administering -2-amine, or a pharmaceutically acceptable salt or soluble compound thereof.

The present invention also provides 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3, To provide 4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or soluble compound thereof.

The present invention also provides 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole for the treatment of behavioral changes. -2-amine, or a pharmaceutically acceptable salt or soluble compound thereof.

In some embodiments, the behavior change is a social behavior change.

In some embodiments, behavioral changes are social atrophy.

In some embodiments, the behavior change is aggressive.

In some embodiments, the behavior change is numb.

Preferably, the KDM1A inhibitor for use in the treatment methods and uses described herein is, for example, compound 5-((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl ) Amino) methyl) -1,3,4-oxadiazole-2-amine (or a pharmaceutically acceptable salt or solvate thereof) is administered orally. Exemplary formulations that can be administered via oral intake are described in more detail below.

As described above, in a preferred embodiment, the present invention provides compound 5-((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl for use in the treatment of behavioral changes. ) -1,3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or soluble compound of the compound. Accordingly, the present invention provides compound 5-((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) as a free base (non-salt form) for use in the treatment of behavioral changes. Methyl) -1,3,4-oxadiazol-2-amine, and the present invention also provides 5-((((1R, 2S) -2- (4- () for use in the treatment of behavioral changes. Benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazol-2-amine.

As described in the Examples, it was surprisingly found that in the context of the present invention, KDM1A inhibitors, such as Compound 1, provide potential therapeutic effects in animal models (humans) of behavioral changes. In particular, the beneficial effects of KDM1A inhibitors have been observed for different types of behavioral changes, particularly aggression, social atrophy and other social behavioral changes.

As illustrated in more detail in Example 3 and FIGS. 1 and 2, KDM1A inhibitors such as Compound 1 have been found to be effective in treating aggressiveness. To test the effect of a compound of interest, such as Compound 1, on aggression, vehicle-treatment identified as showing changed (increased) aggressive behavior compared to control animals evaluated using well-established methods to measure aggressive behavior Among the animals, an animal model (e.g., rodent model) is selected, and then treatment of the aggressive animals with compounds reduces their aggressive behavior compared to vehicle-treated animals, or (normal) of control animals. We evaluated whether aggressive behavior was recovered at the level. Aggressive behavior of animals can be assessed using any standard method for evaluating aggressive behavioral parameters, such as the Resident-Intruder (RI) test, which can be performed in a manner as described in more detail in Example 3.1. have. As an example of a suitable animal model for testing aggression, male SAMP8 mice can be used, and male SAMR1 mice can be used as controls. As illustrated in Examples 3 and 1 and 2, vehicle-treated male SAMP8 mice exhibited significantly increased aggressive behavior compared to the control species SAMR1, which was markedly increased by the total number of attacks, particularly by clinch attack. As shown. Treatment of male SAMP8 mice with KDM1A inhibitors (especially Compound 1) significantly reduces their aggression by the number of attacks (both total and clinch attacks) as illustrated in Figures 1 and 2, which is compound 1-treated SAMP8 mice are restored to SAMR1 levels. Thus, treatment of the KDM1A inhibitor Compound 1 can correct the altered aggressive behavior of SAMP8 mice, supporting the use of the KDM1A inhibitor to treat aggression and related behavioral changes.

In addition to exerting a therapeutic effect on aggression, KDM1A inhibitors such as Compound 1 are also useful in treating other behavioral changes such as social atrophy, as illustrated in Examples 4 and 3 and 4. While mice have a great deal of power, rats are known as more sociable species, so rats are particularly suitable species for assessing social interaction behavior and especially social atrophy. A model suitable for assessing social atrophy is the rat isolation rearing model. In this model, rats are isolated after weaning and have taken away the normal environment premised on their social behavior. Isolation at the developmental stage of rats leads to a lack of interest in behavioral changes, especially social interactions (social avoidance) in adult animals, which can be used as a model for human social atrophy. The animal's social behavior in this model can then be assessed using any standard method for such assessments known in the art, such as the resident-infiltrator test. As illustrated in Examples 4 and 3 and 4, social avoidance parameters were significantly increased in vehicle treated and isolated rats compared to vehicle-treated and non-isolated rats, which was the time without social interaction (Figure 3). And the number of evitations (FIG. 4). The time without social interaction in the isolated rats in FIG. 3 is dose-dependently reduced, and is significantly increased in vehicle-treated and isolated rats in FIG. 4 and normal (i.e., non-isolated rat levels) with treatment with KDM1A inhibitor compound 1 As shown by the decrease in the number of avoidances recovered with), treatment with the KDM1A inhibitor Compound 1 greatly reduces social avoidance in isolated rats. Treatment of KDM1A inhibitors supports the use of KDM1A inhibitors to treat social atrophy and related social behavioral changes by enabling improvement or correction of social avoidance.

The usefulness of KDM1A inhibitors for treating social behavioral changes is further illustrated in Examples 5 and 5 and 6 using three chamber tests (TCT), another widely used social behavioral test. TCT is a commonly used method for measuring social behavior in mice, and is useful for evaluating the effectiveness of compounds to treat social interaction changes using animals with congenital or acquired defects in social behavior. In the TCT test, as described in more detail in Example 5, after acclimatization to the three chamber arena, mice are released into the intermediate chamber and allowed to explore other compartments. In adjacent 'mouse' compartments, mild stimulus mice were placed in a mesh-wire container, while in other adjacent compartments, similar containers were placed without stimulus mice (observation compartment). The tendency for stimulus mice to approach or evade compartments provides a measure of sociality. As illustrated in Examples 5 and 5 and 6, treatment with a KDM1A inhibitor such as Compound 1 can restore social interaction behavior / sociality in subjects exhibiting social interaction changes. As described in Example 5, unlike the control species, SAMR1, female SAMP8 mice show no preference for the "mouse" chamber over the "observation" chamber, and also spend less time exploring new mice, Therefore, it indicates a lack of social behavior. Treatment of female SAMP8 mice with KDM1A inhibitor Compound 1, as shown by recovering both preference for the socialization chamber (mouse chamber) (see Figure 5) and time spent exploring new mice (see Figure 6), SAMP8 The mouse's social interaction behavior / sociality is fully restored to the SAMR1 mouse level.

Importantly, the therapeutic effect of a KDM1A inhibitor such as Compound 1 in the treatment of behavioral changes is a standard analysis to measure sedative or anxiolytic effects such as open field and crosshair high maze, as illustrated in Examples 3 and 4. Can be achieved without generating sedation. Sedation is a serious side effect in many drugs currently used to treat behavioral changes. For example, antipsychotic drugs used to treat aggressiveness generally cause strong sedation. Thus, KDM1A inhibitors, especially Compound 1, are very advantageous over current treatments in that they can be used to treat behavioral changes without causing sedative side effects.

KDM1A inhibitor

As used herein, KDM1A inhibitors are compounds that inhibit KDM1A, particularly human KDM1A.

All types of KDM1A inhibitors can be used in the methods and uses according to the invention.

Preferably, the KDM1A inhibitor used in the methods and uses according to the invention is a small molecule. Both irreversible and reversible KDM1A inhibitors have been reported and can be used in accordance with the present invention. The irreversible KDM1A inhibitors exert their inhibitory activity by covalently binding to the FAD cofactor in the KDM1A active site, and are generally 2-, such as 2- (hetero) arylcyclopropylamino moiety (2- (hetero) arylcyclopropylamino moiety). It is based on a 2-cyclyl-cyclopropylamino moiety. A reversible inhibitor of KDM1A has also been disclosed.

Non-limiting examples of KDM1A inhibitors that can be used in accordance with the present invention include, for example, any one of the compounds disclosed below, any optically active stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof. Includes: WO2010 / 043721, WO2010 / 084160, WO2011 / 035941, WO2011 / 042217, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2013 / 057320, WO2013 / 057322, WO2010 / 143582, US2010-0324147 , WO2011 / 022489, WO2011 / 131576, WO2012 / 034116, WO2012 / 135113, WO2013 / 022047, WO2013 / 025805, WO2014 / 058071, WO2014 / 084298, WO2014 / 086790, WO2014 / 164867, WO2014 / 205213, WO2015 / 021128, WO2015 / 031564, US2015-0065434, WO2007 / 021839, WO2008 / 127734, WO2015 / 089192, CN104119280, CN103961340, CN103893163, CN103319466, CN103054869, WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 123465, WO2015 / 156417, WO2015 / 181380, WO2016 / 123387, WO2016 / 130952, WO2016 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2012 / 071469, WO2013 / 0 33688, WO2014 / 085613, WO2015 / 120281, WO2015 / 134973, WO2015 / 168466, WO2015 / 200843, WO2016 / 003917, WO2016 / 004105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 007736, WO2016 / 034946, WO2016 / 037005, WO2016 / 161282, WO2017 / 004519, WO2017 / 027678, WO2017 / 079476, WO2017 / 079670, WO2017 / 090756, WO2017 / 109061, WO2017 / 116558, WO2017 / 114497, CN106432248, CN106478639, CN106831489, CN106928235, CN105985265, WO2017 / 149463, WO2017 / 157322, WO2017 / 195216, WO2017 / 198780, WO2017 / 215464, WO2018 / 081342, WO2018 / 081343, US2017-0283397, as well as

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. 1,2-치환된 사이클로프로필 고리를 포함하는 상기-기재된 화합물 중 임의의 하나는 상응하는 트랜스-이성질체의 형태(여기서 사이클로프로필 고리의 2개의 치환기가 트랜스-배열인), 또는 각각의 특정 트랜스-이성질체(여기서 사이클로프로필 고리의 2개의 치환기는 도시된 구조에 도시된 것과 동일한 절대 배열(absolute configuration)을 갖거나, 사이클로프로필 고리에서 2개의 치환체는 각각 도시된 구조에 도시된 것과 반대 절대 구조를 갖는) 중 어느 하나의 형태로 사용될 수 있다.

. Any one of the above-listed compounds, including 1,2-substituted cyclopropyl rings, is in the form of the corresponding trans-isomer, wherein the two substituents of the cyclopropyl ring are trans-arranged, or each specific trans- Isomers, wherein the two substituents on the cyclopropyl ring have the same absolute configuration as that shown in the structure shown, or the two substituents on the cyclopropyl ring each have an absolute structure opposite to that shown in the structure shown. ).

Also non-limiting examples of KDM1A inhibitors used in accordance with the invention are described, for example, in K Taeko et al, Bioorg Med Chem Lett 2015, 25 (9): 1925-8. doi: 10.1016 / j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID: 25827526; S Valente et al, Eur J Med Chem. 2015, 94: 163-74. doi: 10.1016 / j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID: 25768700; MN Ahmed Khan et al Med. Chem. Commun., 2015, 6, 407-412, DOI: 10.1039 / C4MD00330F epub 29 Sep 2014; M Pieroni et al, Eur J Med Chem. 2015; 92: 377-386. doi: 10.1016 / j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID: 25585008; V Rodriguez et al, Med. Chem. Commun., 2015, 6, 665-670 DOI: 10.1039 / C4MD00507D, Epub 23 Dec 2014; P Vianello et al, Eur J Med Chem. 2014, 86: 352-63. doi: 10.1016 / j.ejmech.2014.08.068. Epub 2014 Aug 27; DP Mould et al, Med. Res. Rev., 2015, 35: 586-618. doi: 10.1002 / med.21334, epub 24-nov-2014; LY Ma et al, 2015, 58 (4): 1705-16. doi: 10.1021 / acs.jmedchem.5b00037. Epub 2015 Feb 6; SL Nowotarski et al, 2015, 23 (7): 1601-12. doi: 10.1016 / j.bmc.2015.01.049. Epub 2015 Feb 7. PMID: 25725609; CJ Kutz et al Medchemcomm. 2014, 5 (12): 1863-1870 PMID: 25580204; C Zhou et al, Chemical Biology & Drug Design, 2015, 85 (6): 659-671. doi: 10.1111 / cbdd.12461, epub 22-dec-2014; P Prusevich et al, ACS Chem Biol. 2014, 9 (6): 1284-93. doi: 10.1021 / cb500018s. Epub 2014 Apr 7; B Dulla et al, Org Biomol Chem 2013, 11, 3103-3107, doi: 10.1039 / c3ob40217g; JR Hitchin et al, Med ChemCommun, 2013, 4, 1513-1522 DOI: 10.1039 / c3md00226h; And Y Zhou et al, Biorg Med Chem Lett, 2015, online publication 20-Jun-2015, doi: 10.1016 / j.bmcl.2015.06.054.

The irreversible KDM1A inhibitors that can be used in the methods / uses of the present invention include, without limitation, any one of the compounds disclosed below, any optically active stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof. Should: WO2010 / 043721, WO2010 / 084160, WO2011 / 035941, WO2011 / 042217, WO2011 / 131697, WO2012 / 013727, WO2012 / 013728, WO2012 / 045883, WO2013 / 057320, WO2013 / 057322, WO2010 / 143582, US2010-0324147, WO2011 / 131576, WO2012 / 135113, WO2013 / 022047, WO2014 / 058071, WO2014 / 084298, WO2014 / 086790, WO2014 / 164867, WO2015 / 021128; WO2015 / 123408, WO2015 / 123424, WO2015 / 123437, WO2015 / 123465, WO2015 / 156417, WO2015 / 181380, WO2016 / 123387, WO2016 / 130952, WO2016 / 172496, WO2016 / 177656, WO2017 / 027678, CN106045862, WO2014 / 164867 WO2017 / 027678, WO2017 / 079476, WO2017 / 109061, WO2017 / 116558, WO2017 / 114497, CN106831489; K Taeko et al, Bioorg Med Chem Lett. 2015, 25 (9): 1925-8. doi: 10.1016 / j.bmcl.2015.03.030. Epub 2015 Mar 20, PMID: 25827526; S Valente et al, Eur J Med Chem. 2015, 94: 163-74. doi: 10.1016 / j.ejmech.2015.02.060. Epub 2015 Mar 3, PMID: 25768700; MN Ahmed Khan et al Med. Chem. Commun., 2015, 6, 407-412, DOI: 10.1039 / C4MD00330F epub 29 Sep 2014; M Pieroni et al, Eur J Med Chem. 2015; 92: 377-386. doi: 10.1016 / j.ejmech.2014.12.032. Epub 2015 Jan 7. PMID: 25585008; V Rodriguez et al, Med. Chem. Commun., 2015, 6, 665-670 DOI: 10.1039 / C4MD00507D, Epub 23 Dec 2014; or P Vianello et al, Eur J Med Chem. 2014, 86: 352-63. doi: 10.1016 / j.ejmech.2014.08.068. Epub 2014 Aug 27, as well

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; 또는

; or

. 1,2-치환된 사이클로프로필 고리를 포함하는 상기-기재된 화합물 중 임의의 하나는 상응하는 트랜스-이성질체의 형태(여기서 사이클로프로필 고리의 2개의 치환기가 트랜스-배열인), 또는 각각의 특정 트랜스-이성질체(여기서 사이클로프로필 고리의 2개의 치환기는 도시된 구조에 도시된 것과 동일한 절대 배열을 갖거나, 사이클로프로필 고리에서 2개의 치환체는 각각 도시된 구조에 도시된 것과 반대 절대 구조를 갖는) 중 어느 하나의 형태로 사용될 수 있다.

. Any one of the above-listed compounds, including 1,2-substituted cyclopropyl rings, is in the form of the corresponding trans-isomer, wherein the two substituents of the cyclopropyl ring are trans-arranged, or each specific trans- Either one of the isomers, wherein the two substituents on the cyclopropyl ring have the same absolute configuration as shown in the depicted structure, or the two substituents on the cyclopropyl ring each have an absolute structure opposite to that shown in the depicted structure) Can be used in the form of

A reversible KDM1A inhibitor that can be used in the methods / uses of the present invention, without limitation,

WO2007 / 021839, WO2008 / 127734, WO2011 / 022489, WO2012 / 034116, WO2012 / 071469, WO2013 / 025805, US2015 / 0065434, WO2013 / 033688, CN103054869, CN103319466, WO2014 / 085613, CN103893163A, CN103961340, WO2014 / 205213, WO2015 / 031564, WO2015 / 089192, WO2015 / 120281, WO2015 / 134973, WO2015 / 168466, WO2015 / 200843, WO2016 / 003917, WO2016 / 004105, WO2016 / 007722, WO2016 / 007727, WO2016 / 007731, WO2016 / 007736, WO2016 / 034946, In addition to any of the compounds disclosed in WO2016 / 037005, WO2016 / 161282, WO2017 / 004519, WO2017 / 079670, WO2017 / 090756, CN106432248, CN106478639, CN106928235,

;

;

(써클리뎀스타트(seclidemstat));

(Seclidemstat);

Any optically active stereoisomers thereof, or any pharmaceutically acceptable salt or solvate.

In some embodiments, in the methods and uses according to the invention, the KDM1A inhibitor is an irreversible KDM1A inhibitor, preferably a 2- (hetero) arylcyclopropylamino KDM1A inhibitor. As used herein, “2- (hetero) arylcyclopropylamino KDM1A inhibitor” or “2- (hetero) arylcyclopropylamino compound” is substituted with an amino group at position 1 (which is optionally substituted), Refers to a KDM1A inhibitor of a chemical structure comprising a cyclopropyl ring substituted with an aryl group or a heteroaryl group at position 2 (where the aryl or heteroaryl group is optionally substituted).

The ability of the compound to inhibit KDM1A can be tested in vitro using any method known for determining KDM1A inhibition known in the art, such as the method disclosed in Example 2.

Particularly preferred KDM1A inhibitors for use in the methods and uses according to the invention are 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3, 4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or soluble compound thereof.

Other KDM1A inhibitors that can be used in the methods and uses of the present invention include the following compounds, any optically active stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof:

(Trans) -N1-((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (thiazol-5-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

4-(((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanol;

4-(((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexanecarboxamide;

N- (4-(((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) acetamide;

N- (4-(((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) amino) cyclohexyl) methanesulfonamide;

(R) -1- (4-(((trans) -2-phenylcyclopropyl) amino) cyclohexyl) pyrrolidin-3-amine;

N1-((trans) -2- (4'-chloro- [1,1'-biphenyl] -4-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (3'-chloro- [1,1'-biphenyl] -4-yl) cyclopropyl) cyclohexane-1,4-diamine;

4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-ol;

N- (4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl)-[1.1'-biphenyl] 3-yl) methanesulfonamide;

N1-((trans) -2- (4-((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4-((3-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4-((4-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-methyl-N4-((trans) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

N1-methyl-N4-((trans) -2- (3 '-(trifluoromethyl)-[1.1'-biphenyl] -4-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -N4-methylcyclohexane-1,4-diamine;

N1-((trans) -2-phenylcyclopropyl) cyclobutane-1,3-diamine;

N1-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) cyclobutane-1,3-diamine;

N1-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) cyclobutane-1,3-diamine;

N1-((trans) -2-phenylcyclopropyl) -2,3-dihydro-1H-indene-1,3-diamine;

N1-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) -2,3-dihydro-1H-indene-1 , 3-diamine;

N1-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) -2,3-dihydro-1H-indene-1,3-diamine;

N1-((trans) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

N1-((1S, 2S) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

N1-((1R-2R) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

1-methyl-N4-((trans) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

4- (aminomethyl) -N-((trans) -2-phenylcyclopropyl) cyclohexanamine;

N1-((trans) -2-phenylcyclopropyl) cyclohexane-1,3-diamine;

N1-((cis) -2-phenylcyclopropyl) cyclohexane-1,4-diamine;

Tert-butyl (4-(((trans) -2-phenylcyclopropyl) amino) cyclohexyl) carbamate;

1-ethyl-3- (4-(((trans) -2-phenylcyclopropyl) amino) cyclohexyl) urea;

4-morpholino-N-((trans) -2-phenylcyclopropyl) cyclohexanamine;

N1-((trans) -2- (4-bromophenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2- (o-tolyl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1,4-diamine;

4- (2-((4-aminocyclohexyl) amino) cyclopropyl) phenol;

N1- (2- (2-fluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1- (2-methyl-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

(R) -1- (4-(((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) amino) cyclohexyl) Pyrrolidin-3-amine;

(Cis) -N1-((1S, 2R) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) cyclohexane-1,4- Diamine;

(Trans) -N1-((1S, 2R) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclo-propyl) cyclohexane-1,4 -Diamine;

(Cis) -N1-((1R, 2S) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclo-propyl) cyclohexane-1,4 -Diamine;

(Trans) -N1-((1R, 2S) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclo-propyl) cyclohexane-1,4 -Diamine;

N1-((trans) -2- (4-cyclopropylphenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (pyridin-3-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (1H-indazol-6-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (1H-pyrazol-5yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

3- (5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) thiophen-2-yl) phenol;

3- (5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenol;

3- (5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -5-methoxybenzonitrile;

5- (5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) -2-methylphenol;

N- (4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) -6-methoxy- [1,1'-biphenyl] -3-yl) methanesulfonamide;

N- (3- (5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) thiazol-2-yl) phenyl) -2-cyanobenzenesulfonamide;

N- (4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) -2-cyanobenzenesulfonamide;

6-amino-N- (4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) pyridine-3-sulfone Amide;

N- (4 '-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) piperazin-1-sulfonamide;

N1-((cis) -2-fluoro-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4-((3- (piperazin-1-yl) benzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (pyridin-3-ylmethoxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (6-((3-methylbenzyl) amino) pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

3-((5-((trans) -2-((4-aminocyclohexyl) amino) cyclopropyl) pyridin-2-yl) amino) benzonitrile;

N1-((trans) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (o-tolyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4- (trifluoromethyl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (4-methoxyphenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (2-fluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

N1-((trans) -2-methyl-2-phenylcyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1S, 2R) -2- (pyridin-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1,3-diamine;

(Trans) -N1-((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1,3-diamine;

(Cis) -N1-((1R, 2S) -2-phenylcyclopropyl) cyclobutane-1,3-diamine;

(Trans) -N1-((1S, 2R) -2-phenylcyclopropyl) cyclobutane-1,3-diamine;

(Cis) -N1-((1S, 2R) -2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2- (3,4-difluorophenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4, -diamine;

(Trans) -N1-((1R, 2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2- (naphthalen-2-yl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1R, 2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2- (4- (1H-pyrazol-5-yl) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N- (4 '-((1R, 2S) -2-(((cis) -4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) piperazine- 1-sulfonamide;

N- (4 '-((1S, 2R) -2-(((trans) -4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) piperazine- 1-sulfonamide;

N- (4 '-((1S, 2R) -2-(((cis) -4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) piperazine- 1-sulfonamide;

N- (4 '-((1R, 2S) -2-(((trans) -4-aminocyclohexyl) amino) cyclopropyl)-[1,1'-biphenyl] -3-yl) piperazine- 1-sulfonamide;

(Cis) -N1-((1S, 2R) -2- (4-((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1R, 2S) -2- (4-((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Cis) -N1-((1R, 2S) -2- (4-((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

(Trans) -N1-((1S, 2R) -2- (4-((2-fluorobenzyl) oxy) phenyl) cyclopropyl) cyclohexane-1,4-diamine;

N-((trans) -2-phenylcyclopropyl) piperidin-4-amine;

N-((1S, 2R) -2-phenylcyclopropyl) piperidin-4-amine;

N-((1R, 2S) -2-phenylcyclopropyl) piperidin-4-amine;

N-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (6- (3- (trifluoromethyl) phenyl) pyridin-3-yl) cyclopropyl) tetrahydro-2H-pyran-4-amine;

N-((trans) -2- (pyridin-3-yl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (thiazol-5-yl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) piperidin-4-amine;

N-((trans) -2-phenylcyclopropyl) piperidin-3-amine;

N-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) piperidin-3-amine;

N-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) piperidin-3-amine;

N-((trans) -2-phenylcyclopropyl) pyrrolidin-3-amine;

N-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) pyrrolidin-3-amine;

N-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) pyrrolidin-3-amine;

N-((trans) -2-phenylcyclopropyl) azetidin-3-amine;

N-((trans) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) azetidin-3-amine;

N-((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) azetidin-3-amine;

N-((trans) -2-phenylcyclopropyl) azepan-3-amine;

N-((trans) -2-phenylcyclopropyl) -8-azabicyclo [3.2.1] octan-3-amine;

N-((trans) -2-phenylcyclopropyl) -3-azabicyclo [3.2.1] octan-8-amine;

N-((trans) -2-phenylcyclopropyl) decahydroquinolin-4-amine;

N-((trans) -2-phenylcyclopropyl) -1,2,3,4-tetrahydroquinolin-4-amine;

N-((trans) -2-phenylcyclopropyl) -3-azaspiro [5.5] undecan-9-amine;

N-((trans) -2-phenylcyclopropyl) -2-azaspiro [4.5] decane-8-amine;

N-((trans) -2-phenylcyclopropyl) -2,3-dihydrospiro [inden-1,4'-piperidine] -3-amine;

N-((1S, 2R) -2- (4- (benzyloxy) phenyl) cyclopropyl) piperidin-4-amine;

N-((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) piperidin-4-amine;

N-((1S, 2R) -2- (pyridin-3-yl) cyclopropyl) piperidin-4-amine;

N-((1R, 2S) -2- (pyridin-3-yl) cyclopropyl) piperidin-4-amine;

N-((1S, 2S) -2- (thiazol-5-yl) cyclopropyl) piperidin-4-amine;

N-((1R, 2R) -2- (thiazol-5-yl) cyclopropyl) piperidin-4-amine;

N-((1S, 2R) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) piperidin-4-amine;

N-((1R, 2S) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropyl) piperidin-4-amine;

N-((trans) -2-phenylcyclopropyl) -7-azaspiro [3.5] nonan-2-amine;

N- (2- (o-tolyl) cyclopropyl) piperidin-4-amine;

N- (2- (2-fluorophenyl) cyclopropyl) piperidin-4-amine;

N- (2- (3,4-difluorophenyl) cyclopropyl) piperidin-4-amine;

N- (2- (4-methoxyphenyl) cyclopropyl) piperidin-4-amine;

N- (2- (naphthalen-2-yl) cyclopropyl) piperidin-4-amine;

N- (2-methyl-2-phenylcyclopropyl) piperidin-4-amine;

N- (6-methoxy-4 '-((trans) -2- (piperidin-4-ylamino) cyclopropyl)-[1,1'-biphenyl] -3-yl) methanesulfonamide;

N- (4 '-((trans) -2- (piperidin-4-ylamino) cyclopropyl)-[1,1'-biphenyl] -3-yl) propane-2-sulfonamide;

1- (methylsulfonyl) -N-((trans) -2-phenylcyclopropyl) piperidin-4-amine;

1- (4-(((trans) -2- (4-bromophenyl) cyclopropyl) amino) piperidin-1-yl) ethanone;

4-(((trans) -2- (4-bromophenyl) cyclopropyl) amino) piperidine-1-carboxamide;

N-((trans) -2- (4-bromophenyl) cyclopropyl) tetrahydro-2H-pyran-4-amide;

2,2,6,6-tetramethyl-N-((trans) -2-phenylcyclopropyl) piperidin-4-amine;

1-methyl-N-((trans) -2-phenylcyclopropyl) piperidin-4-amine;

1-isopropyl-N-((trans) -2-phenylcyclopropyl) piperidin-4-amine;

N-((trans) -2-phenylcyclopropyl) -1- (2,2,2-trifluoroethyl) piperidin-4-amine;

N-((trans) -2-phenylcyclopropyl) -1- (pyridin-4-yl) piperidin-4-amine;

4-(((trans) -2- (4-bromophenyl) cyclopropyl) amino) tetrahydro-2H-thiopyran 1,1-dioxide;

N-((trans) -2-fluoro-2-phenylcyclopropyl) piperidin-4-amine;

N-((1S, 2S) -2-fluoro-2-phenylcyclopropyl) piperidin-4-amine;

N-((1R, 2R) -2-fluoro-2-phenylcyclopropyl) piperidin-4-amine;

N-((trans) -2- (naphthalen-2-yl) cyclopropyl) piperidin-4-amine;

N-((trans) -2-methyl-2-phenylcyclopropyl) piperidin-4-amine;

N-((trans) -2- (o-tolyl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (2-fluorophenyl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (3,4-difluorophenyl) cyclopropyl) piperidin-4-amine;

N-((trans) -2- (4-methoxyphenyl) cyclopropyl) piperidin-4-amine;

(Trans) -2-phenyl-N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -2-phenyl-N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(Trans) -2-phenyl-N- (2- (tetrahydro-2H-pyran-4-yl) ethyl) cyclopropanamine;

(Trans) -2- (4'-chloro- [1,1'-biphenyl] -4-yl) -N- (2- (tetrahydro-2H-pyran-4-yl) ethyl) cyclopropanamine;

(Trans) -N- (piperidin-4-ylmethyl) -2- (pyridin-3-yl) cyclopropanamine;

(Trans) -N- (piperidin-4-ylmethyl) -2- (thiazol-5-yl) cyclopropanamine;

(Trans) -N- (piperidin-4-ylmethyl) -2- (3'-trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropanamine;

(Trans) -2- (4- (benzyloxy) phenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -N- (2- (piperidin-4-yl) ethyl) -2- (pyridin-3-yl) cyclopropanamine;

(Trans) -N- (2- (piperidin-4-yl) ethyl) -2- (thiazol-5-yl) cyclopropanamine;

(Trans) -N- (2- (piperidin-4-yl) ethyl) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropane Amine;

(Trans) -2- (4- (benzyloxy) phenyl) -N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(1S, 2R) -2-phenyl-N- (piperidin-4-ylmethyl) cyclopropanamine;

(1R, 2S) -2-phenyl-N- (piperidin-4-ylmethyl) cyclopropanamine;

(1S, 2R) -2-phenyl-N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(1R, 2S) -2-phenyl-N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(1S, 2R) -N- (piperidin-4-ylmethyl) -2- (pyridin-3-yl) cyclopropanamine;

(1R, 2S) -N- (piperidin-4-ylmethyl) -2- (pyridin-3-yl) cyclopropanamine;

(1S, 2S) -N- (piperidin-4-ylmethyl) -2- (thiazol-5-yl) cyclopropanamine;

(1R, 2R) -N- (piperidin-4-ylmethyl) -2- (thiazol-5-yl) cyclopropanamine;

(1S, 2R) -N- (piperidin-4-ylmethyl) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropanamine;

(1R, 2S) -N- (piperidin-4-ylmethyl) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) cyclopropanamine;

(1S, 2R) -2- (4- (benzyloxy) phenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(1R, 2S) -2- (4- (benzyloxy) phenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(1S, 2R) -N- (2- (piperidin-4-yl) ethyl) -2- (pyridin-3-yl) cyclopropanamine;

(1R, 2S) -N- (2- (piperidin-4-yl) ethyl) -2- (pyridin-3-yl) cyclopropanamine;

(1S, 2S) -N- (2- (piperidin-4-yl) ethyl) -2- (thiazol-5-yl) cyclopropanamine;

(1R, 2R) -N- (2- (piperidin-4-yl) ethyl) -2- (thiazol-5-yl) cyclopropanamine;

(1S, 2R) -N- (2- (piperidin-4-yl) ethyl) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) Cyclopropanamine;

(1R, 2S) -N- (2- (piperidin-4-yl) ethyl) -2- (3 '-(trifluoromethyl)-[1,1'-biphenyl] -4-yl) Cyclopropanamine;

(1S, 2R) -2- (4- (benzyloxy) phenyl) -N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(1R, 2S) -2- (4- (benzyloxy) phenyl) -N- (2- (piperidin-4-yl) ethyl) cyclopropanamine;

(Trans) -2-phenyl-N- (pyrrolidin-3-ylmethyl) cyclopropanamine;

(Trans) -2- (4-((2-fluorobenzyl) oxy) phenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -N- (azetidin-3-ylmethyl) -2-phenylcyclopropanamine;

(Trans) -2- (4-cyclopropylphenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -N- (piperidin-4-ylmethyl) -2- (4- (pyridin-3-yl) phenyl) cyclopropanamine;

(Trans) -2- (4- (1H-pyrazol-5-yl) phenyl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -2- (naphthalen-2-yl) -N- (piperidin-4-ylmethyl) cyclopropanamine;

2-methyl-2-phenyl-N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -2-methyl-2-phenyl-N- (piperidin-4-ylmethyl) cyclopropanamine;

(Trans) -2- (4- (benzyloxy) phenyl) -N-((1-methylpiperidin-4-yl) methyl) cyclopropanamine;

4-((4-((((1R, 2S) -2-phenylcyclopropyl) amino) methyl) piperidin-1-yl) methyl) benzoic acid;

1-((4- (methoxymethyl) -4-(((1R, 2S) -2-phenylcyclopropylamino) methyl) piperidin-1-yl) methyl) cyclobutanecarboxylic acid;

N-[(2S) -5-{[(1R, 2S) -2- (4-fluorophenyl) cyclopropyl] amino} -1- (4-methylpiperazin-1-yl) -1-oxopentane -2-yl] -4- (1H-1,2,3-triazol-1-yl) benzamide;

4- [2- (4-amino-piperidin-1-yl) -5- (3-fluoro-4-methoxy-phenyl) -1-methyl-6-oxo-1,6-dihydro- Pyrimidin-4-yl] -2-fluorobenzonitrile;

(T-3775440);

(T-3775440);

(써클리뎀스타트(seclidemstat));

(Seclidemstat);

;

;

;

;

; 또는

; or

.

.

Pharmaceutical Formulations

It is also possible to administer a KDM1A inhibitor, for example Compound 1, as such, for direct use in therapy, but is typically administered in the form of a pharmaceutical composition, the composition being one or more pharmaceutical Included with acceptable excipients or carriers. Any reference to a KDM1A inhibitor herein is not only a reference to such a compound, i.e. a non-salt form (e.g. as a free base) or a corresponding compound in their pharmaceutically acceptable salt or solvate form. , Reference to a pharmaceutical composition comprising the compound and one or more pharmaceutically acceptable excipients or carriers.

The KDM1A inhibitor can be administered by any means that fulfill its intended purpose. Examples include oral, parenteral (eg, intravenous, subcutaneous or intracranial), or administration by topical route.

For oral delivery, the active compound is a pharmaceutically acceptable carrier, such as a binder (e.g. gelatin, cellulose, gum tragacanth), excipients (e.g. starch, lactose), lubricants (e.g. For example, magnesium stearate, silicon dioxide), disintegrating agents (e.g. alginate, primogel, and corn starch), and sweetening or flavoring agents (e.g. glucose, sucrose, saccharin, methyl salicylate) , And peppermint). The formulations can be delivered orally in the form of sealed gelatin capsules or compressed tablets. Capsules and tablets can be prepared by any conventional technique. The capsules and tablets can also be coated with various coating agents known in the art to modify the flavor, taste, color and shape of the capsules and tablets. In addition, liquid carriers such as fatty oils can also be included in capsules.

Suitable oral formulations may also be in the form of suspensions, syrups, chewing gum, wafers, elixirs, and the like. If desired, customary agents may also be included in the modification of flavor, taste, color, and shape in special forms. In addition, for convenient administration by intestinal supply tubes in patients who cannot swallow, the active compounds can be dissolved in acceptable lipophilic vegetable oil vehicles such as olive oil, corn oil and safflower oil.

The active compounds can also be administered in the form of solutions or suspensions, or lyophilized parenterally which can be converted to solutions or suspensions prior to use. In such formulations, diluents or pharmaceutically acceptable carriers can be used, such as sterile water and physiological saline buffers. Other conventional solvents, pH buffers, stabilizers, antibacterial agents, surfactants, and antioxidants can all be included. For example, useful ingredients may include sodium chloride, acetate, citrate or phosphate buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. . Parenteral formulations can be stored in any conventional container, such as vials and ampoules.

For topical administration, the compounds can be formulated as lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Accordingly, one or more thickeners, wetting agents, and stabilizers can be included in the formulation. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beads wax or mineral oil, lanolin, squalene, and the like. Special forms of topical administration are delivered by transdermal patches. Methods of preparing transdermal patches are described, for example, in Brown, et al. (1988) Ann. Rev. Med . 39: 221-229 (incorporated by reference herein).

Subcutaneous transplantation for sustained release of the compound may also be a suitable route of administration. This route entails surgical procedures in which the active compound in any suitable formulation is implanted into the subcutaneous space, eg, the abdominal wall. See, eg, Wilson et al . (1984) J. Clin. Psych. 45: 242-247. Hydrogels can be used as carriers for the sustained release of the active compounds. Hydrogels are generally known in the art. The hydrogel is typically prepared by crosslinking a high molecular weight biocompatible polymer into a network, which expands in water to form a gel-like material. Preferably, the hydrogel is biodegradable or bioabsorbable. For the purposes of the present invention, a hydrogel made of polyethylene glycol, collagen or poly (glycolic-co-L-lactic acid) may be useful. See, eg, Phillips et al . (1984) J. Pharmaceut. Sci. , 73: 1718-1720.

The active compounds can also be conjugated to water soluble non-immunogenic non-peptide high molecular weight polymers to form polymer conjugates. For example, the compound is covalently bound to polyethylene glycol to form a conjugate. Typically, such conjugates exhibit improved solubility, stability, and reduced toxicity and immunogenicity. Therefore, when administered to a patient, the active compound in the conjugate may have a longer half-life in the body and may exhibit better efficacy. In general, see Burnham (1994) Am. J. Hosp. Pharm . 15: 210-218. Pegylated proteins are currently used in protein replacement therapy and other therapeutic uses. For example, PEGylated interferon (PEG-INTRON A®) is used clinically in the treatment of hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is being used in the treatment of severe combined immunodeficiency syndrome (SCID). PEGylated L-asparaginase (ONCAPSPAR®) is being used in the treatment of acute lymphoblastic leukemia (ALL). It is preferred that the covalent bond between the polymer and the active compound and / or the polymer itself is degradable by hydrolysis under physiological conditions. Such conjugates, known as “prodrugs”, can readily release the active compound into the body. Controlled release of the active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art. Other pharmaceutically acceptable prodrugs of the compound include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases , Amino acid conjugates, phosphate esters, metal salts and sulfonate esters.

Liposomes can also be used as carriers for the active compounds of the invention. Liposomes are micelles made from various lipids, for example cholesterol, phospholipids, fatty acids and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compound and increase its stability. Methods of preparing liposomal suspensions containing the active ingredient are generally known in the art. For example, US Patent No. 4,522,811; See Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976).

Pharmaceutical compositions, such as oral or parenteral compositions, can be formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, “single dosage form” refers to physically discrete units suitable as unit dosages for administration to an individual, each unit in association with one or more suitable pharmaceutical carriers, the desired therapeutic effect. It contains a predetermined amount of active ingredient calculated to produce.

In therapeutic applications, the pharmaceutical composition should be administered in a manner appropriate to the disease to be treated, as determined by those skilled in the medical arts. The appropriate dosage and suitable duration and frequency of administration can be determined by factors such as the patient's condition, the type and severity of the disease, the specific form of the active ingredient, the method of administration, and the like. In general, appropriate dosages and dosing regimens are of therapeutic benefit, such as improved clinical outcomes, such as more frequent complete or partial relief, or longer disease-free and / or overall survival, or suffering. Provide a sufficient amount of a pharmaceutical composition to provide a reduction, or any other objectively identifiable improvement as noted by the clinician. In general, effective dosages can be assessed or estimated using test models such as dose-response curves derived from in vitro or animal model test systems as illustrated in the Examples.

The pharmaceutical composition of the present invention may be included in a container, pack or dispenser along with instructions for administration.

KDM1A inhibitors such as Compound 1, when administered orally, have been found to be effective in the treatment of behavioral changes as being oral, as illustrated in Examples 3 and 4. Thus, KDM1A inhibitors (eg, Compound 1) are administered by the oral route for the treatment of behavioral changes.

The present invention also encompasses the use of KDM1A inhibitors in which one or more atoms are replaced by a particular isotope of the corresponding atom. For example, the present invention includes the use of KDM1A inhibitors in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced with deuterium atoms (ie, ² H; also referred to as “D”). . Thus, the present invention also includes a deuterium-rich KDM1A inhibitor. Naturally occurring hydrogen is an isotope mixture comprising about 99.98 mol% hydrogen 1 (1H) and about 0.0156 mol% deuterium ( ² H or D). The content of deuterium at one or more hydrogen sites of the KDM1A inhibitor can be increased using deuteration techniques known in the art. For example, a reactant or precursor used in the synthesis of the KDM1A inhibitor or KDM1A inhibitor may be subjected to H / D exchange reaction using, for example, heavy water (D ₂ O). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem , 20 (18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals , 53 (11-12), 635-644, 2010; Modvig A et al., J Org Chem , 79, 5861-5868, 2014. The content of deuterium can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the KDM1A inhibitor used in accordance with the invention is not enriched with deuterium. Therefore, it is preferable that a hydrogen atom or ¹ H hydrogen atom that occurs naturally in the KDM1A inhibitor is present. In general, it is preferred that none of the atoms in the KDM1A inhibitor used in accordance with the present invention is replaced with a specific isotope.

A pharmaceutical composition comprising a KDM1A inhibitor or a KDM1A inhibitor used in accordance with the present invention is a single therapy (e.g., not administering any additional therapeutic agents simultaneously, or simultaneously administering additional therapeutic agents for the same behavioral changes to be treated with the KDM1A inhibitors). No). Thus, a KDM1A inhibitor or a pharmaceutical composition comprising a KDM1A inhibitor can be used in a single treatment treatment of behavioral changes (e.g., no other therapeutic agent is administered for the same behavioral change until treatment is terminated with the KDM1A inhibitor). However, KDM1A inhibitors or pharmaceutical compositions comprising KDM1A inhibitors can also be administered in combination with one or more additional therapeutic agents. When a KDM1A inhibitor is used in combination with a second therapeutic agent that is active against the same behavioral change, the dosage of each compound is different when the corresponding compound is used alone, particularly when a small dose of each compound can be used. You can. Combination of one or more additional therapeutic agents with a KDM1A inhibitor may result in simultaneous / concomitant administration of the KDM1A inhibitor and the additional therapeutic agent (s) (single medicinal or separate medicinal agent), or KDM1A inhibitor and additional therapeutic agent (s). Sequential / separate administration. If administration is sequential, a KDM1A inhibitor or one or more additional therapeutic agents may be administered first. When administration is simultaneous, one or more additional therapeutic agents can be included in the same pharmaceutical formulation as a KDM1A inhibitor, or can be administered in one or more other (separate) pharmaceutical formulations (which can be administered via the same or different routes of administration). have.

Justice

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Unless otherwise defined, the following definitions apply throughout the specification and claims of the present invention.

“Patient” or “subject” for the purposes of the present invention includes both humans and other animals, particularly mammals, and other organisms. Accordingly, the methods and uses of the invention are applicable to both human therapeutic and veterinary applications. In a preferred aspect, the individual or patient is a mammal, and in the most preferred aspect, the individual or patient is a human.

The term "abnormal" refers to something other than normal, average or expected.

The term "inappropriate" indicates that something is inconsistent with social standards and / or expectations.

The term "pathological" refers to something, for example a phenomenon or condition, that constitutes the disease state, is altered or caused by the disease, or is associated with the disease.

The terms "treatment", "treating" and the like are used herein to mean generally obtaining the desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease (herein, behavioral change) or symptoms thereof, and / or partially or partially symptomatic or side effects of a disease (ie, behavioral change) and / or disease It may be completely cured or improved, or it may be therapeutic in terms of partially or completely stopping the progression of symptoms or side effects due to the disease and / or disease. As used herein, the term “treatment” includes any treatment of a disease (ie behavioral change) in a patient and includes, without limitation, any one or more of the following: (a) behavior Preventing behavioral changes in patients who are / are at risk of developing changes; (b) delay the onset of behavioral changes; (c) inhibiting behavior change, i.e. preventing, delaying or slowing the development / progress of behavior change; Or (d) alleviating behavioral changes, ie causing (complete or partial) regression, correction or alleviation of behavioral changes. The present invention specifically and explicitly relates to each of these types of treatment.

As used herein, “therapeutically effective amount” refers to an amount sufficient to produce a desired biological effect (eg, therapeutic effect) in an individual. Thus, a therapeutically effective amount of a compound is an amount sufficient to treat a disease, and / or delay the onset or progression of the disease, and / or relieve one or more symptoms of the disease when administered to a patient suffering from or susceptible to the disease. You can.

As used herein, “pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acid and / or base of the specified compound and is biologically or otherwise undesirable. The compound may be sufficiently acidic, sufficiently basic, or have both functional groups, and thus react with a number of inorganic or organic bases, and any of the inorganic and organic acids to form pharmaceutically acceptable salts. Exemplary pharmaceutically acceptable salts are salts prepared by the reaction of a compound of the invention with an inorganic or organic acid, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite , Phosphate, monohydrophosphate, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, nitrate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyl Late, caproate, hepatonate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexine-1,5-dio Eight, benzoate, chlorobenzoate, methylbenzoate, dynitrobenzoate, hydroxybene Zoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methane-sulfo Nate, ethane-sulfonate, propanesulfonate, benzenesulfonate, toluenesulfonate, trifluoromethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, pyruvate, stearate, as Corbate, or salicylate. When the compounds of the present invention have acidic moieties, suitable pharmaceutically acceptable salts thereof include alkali metal salts, such as sodium or potassium salts; Alkaline earth metal salts, such as calcium or magnesium salts; And salts formed with suitable organic ligands, such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine, and the like. Pharmaceutically acceptable salts are well known in the art.

As used herein, “pharmaceutically acceptable solvate” refers to a complex of solutes and variable stoichiometry formed by pharmaceutically acceptable solvents such as water, ethanol, and the like. Complexes with water are known as hydrates. It is understood that the present invention includes pharmaceutically acceptable solvates of any KDM1A inhibitors in non-salt form and in the form of a pharmaceutically acceptable salt thereof.

As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is used in the formulation of a non-API (API refers to the active pharmaceutical ingredient) material, eg a drug. Refers to disintegrants, binders, fillers and lubricants. These substances are generally safe for human administration according to established government standards, including those issued by the U.S. Food and Drug Administration and European health authorities. Pharmaceutically acceptable carriers or excipients are well known in the art.

As used herein, "small molecule" refers to an organic compound having a molecular weight of less than 900 Daltons, preferably less than 500 Daltons. Molecular weight is the mass of a molecule and is calculated by multiplying the atomic weight of each component by the number of atoms of the corresponding element in the molecular formula.

As used herein, the terms "comprising" (or "comprise", "comprises", "contain", "contains", Or "containing", unless expressly stated otherwise or contradicted by context, "including, inter alia," that is, "including any of the additional optional elements ... (containing, among further optional elements, ...) ". In addition, the term also includes the narrow meanings of “consisting essentially of” and “consisting of”. For example, the term "A comprising B and C" has the meaning of "particularly A containing B and C", wherein A may have additional optional elements (eg, "B, C And A containing D). This term means “A consisting essentially of B and C” and “A consisting of B and C” (ie, components other than B and C are (Not included in A).

As used herein, the terms "a", "an", and "the" are "one or more" and "unless expressly stated otherwise or contradictory in context. "At least one". Thus, for example, “a (a)” KDM1A inhibitor may be interpreted to refer to a composition comprising “one or more” KDM1A inhibitors.

Example

The following examples illustrate various aspects of the invention. Of course, it should be understood that the examples are only illustrative of specific embodiments of the invention and do not limit the scope of the invention. The results are displayed and described in the drawings and drawing legends.

Example 1: Materials

Compound 1 (or Comp. 1) is (-) 5-(((((trans) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole Compound 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazole-2- also known as -2-amine Amine, and the chemical structure is shown below.

This compound can be obtained as disclosed in WO2012 / 013728.

Example 2: Analysis of KDM1A inhibitors in vitro

The inhibitory activity of a compound against KDM1A can be determined using the method described below.

Human recombinant KDM1A protein (GenBank accession no NM_015013, amino acid 158-end GST tagged at the N-terminus, MW: 103 kDa) was used.

Serial 3-fold dilutions of test compounds ranging from 30 μM to 1 nM were preincubated on ice with human recombinant KDM1A enzyme (BPS Bioscience, Ref. 50100) for 15 min in assay buffer (50 mM sodium phosphate pH 7.4). Each concentration of inhibitor was tested in duplicate. The enzyme reaction was initiated in KDM1A appK _M by the addition of dimethyl H3K4 peptide substrate (Anaspec, Ref. 63677). After incubation at 37 ° C for 30 minutes, Amplex Red reagent and horseradish peroxidase (HRP) solution were added to detect H ₂ O ₂ formed in the enzymatic reaction, followed by recommendations provided by the supplier (Invitrogen). The mixture was incubated in the dark at room temperature for 5 minutes, and the conversion of Amplex Red reagent to solid fluorescent resorufin was analyzed using an Infinite F200 Tecan fluorescence microplate reader (λ excitation = 540 nm, λ emission = 590 nm). The maximum demethylase activity of KDM1A was obtained in the absence of inhibitors, and background fluorescence was corrected in the absence of KDM1A. The IC ₅₀ value of each inhibitor was calculated with GraphPad Prism5 Software in at least two independent trials.

Compound 1 is a KDM1A inhibitor, as represented by an average IC ₅₀ value of 101 ± 40 nM obtained from the KDM1A assay described herein.

Example 3: Evaluation of the effect of KDM1A inhibitors on aggressive behavior

The effect of KDM1A inhibitor Compound 1 on aggressive behavior was evaluated in SAMP8 male mice using a Resident-Invader (RI) test. The RI test is a standardized method of measuring social behavior, particularly aggressive behavior in an anti-natural environment.

3.1 Method

The SAM mouse model was developed from AKR / J mouse species from Kyoto University. SAMP8 liters showed severe aging and were selected to further investigate and propagate these properties. SAMR1 liters showed normal aging and was selected as an aging-resistant species.

In this study, male SAMP8 animals were treated with vehicle (n = 5), 0.32 mg / kg / day of compound 1 (n = 8), or 0.96 mg / kg / day of compound (n = 8) from 5 months of age. Following weekly treatment, RI testing was performed. Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or Compound 1 was administered to drinking water. SAMR1 mice treated with vehicle were included as a control (n = 6). All drugs were administered with drinking water and diluted with vehicle. Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

Resident-invader (RI) testing was performed as follows: Subjects (residents) were maintained in their home cages for one week without changing bedding. On the day of the test, fairly young and small subjects (invaders, 90 day old C57BL6 mice) were introduced into the resident home cage. Sessions (20 minutes) were video-recorded, lateral threats, clinch attacks, maintenance as social interactions (tested parameters: social interactions and parenting) and aggressive behaviors (tested parameters: sum of three measured aggressive behavioral parameters) Behavior and total attack) were analyzed as visual impairment experimenters on treatment.

Statistical analysis: SAMR1 and SAMP8 vehicle groups were compared by t-test. Among the SAMP8 groups, other treatments were compared by one-way ANOVA using Dunnet and SNK post-Hoc analysis.

3.2 Results

When comparing the aggressive behavior of SAMP8 mice in the RI test to that of the SAMR1 mice, the total number of attacks, especially the number of clinch attacks, in vehicle-treated SAMP8 mice compared to vehicle-treated SAMR1 mice, as shown in FIGS. 1 and 2. Significantly increased, indicating that SAMP8 male mice exhibited altered (increased) aggressive behavior compared to the reference species SAMR1. Treatment of SAMP8 mice with Compound 1, as shown in Figures 1 and 2, reduced the number of SAMP8 mice to SAMR1 levels. Thus Compound 1 dramatically reduced aggression in SAMP8 mice, correcting the animal's altered aggressive behavior.

Vehicle-treated SAMP8 animals showed no significant difference in time spent in social interactions compared to vehicle-treated DAMR1 mice. No significant difference was observed in the number of rearing in vehicle-treated SAMP8 and SAMR1 mice, and treatment with Compound 1 did not affect this reading in SAMP8 mice.

3.3 The effect of KDM1A inhibitors on aggressive behavior is not due to sedation

To confirm that the effect of Compound 1 on the aggressive action of SAMP8 is due to the direct effect of the compound on the aggressiveness of animals and is not caused by the potential sedative effect of the compound, on the anxiety and motor activity of male SAMP8 mice The effect of Compound 1 was studied using the open field (OF) and cross high maze (EPM) tests described below.

3.3.1 Method

Animals (n = 8 / group) were treated with vehicle, 0.32 or 0.96 mg / kg / day Compound 1 from 5 months of age, and OF and EMP tests were sequentially performed at 1 week intervals up to 7 months of treatment.

Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or KDM1A inhibitor (Compound 1) was administered to drinking water. Vehicle treated SAMR1 mice were included as a control (n = 8). All drugs were administered through drinking water and diluted in vehicle. Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

OF and EPM tests were performed as follows:

Open Field (OF): To analyze spontaneous search behavior, a 50 x 50-cm white plastic arena with a 25-cm high wall was used. The bottom of the device was divided into 25 identical squares. The motion of each animal was video-recorded for 5 minutes. Motor activity was analyzed by video-tracking the captured images using SMART ^® (v3.0, PanLab, SLU, Spain).

Cross-shaped high maze (EPM): The EMP consists of three arms connected to the central square and perpendicular to each other, maintaining a height of 50 cm from the floor. Two of the opposite arms had high walls (enclosed arms, 30 x 5 x 15 cm), but the other two arms were open arms (30 x 5 x 0 cm). Animals were placed facing the closed arms, and the movements were video-recorded for 5 minutes and analyzed video-traced using SMART ^® (v3.0, PanLab, SLU, Spain).

Statistical analysis: SAMR1 and SAMP8 vehicle groups were compared by t-test. Among the SAMP8 group, different treatments were compared by one-way ANOVA using Dunnet and SNK post-Hoc analysis.

3.3.2 Results

No significant differences were observed between vehicle-treated SAMR1 mice and vehicle-treated SAMP8 mice in the OF test, and treatment with compound 1 had no significant effect on motor activity or time spent in the central zone. SAMP8 mice had significantly increased time in the open arms of EPM compared to SAMR1 mice, but this behavior was not significantly altered by Compound 1. Thus, Compound 1 had no anxiolytic or sedative action in SAMP8 mice.

In summary, the data and results obtained in Example 3 show that KDM1A inhibitor Compound 1 was administered by mice for long-term treatment at a dose that was highly resistant and significantly reduced aggression, but did not act as a sedative or anxiolytic in SAMP8 mice. Shows that it did. Thus, Example 3 supports the discovery that KDM1A inhibitors, especially Compound 1, can be used for the treatment of behavioral disorders such as aggressiveness without causing sedation.

Using the protocol described in Example 3, the effect of improving behavioral changes (e.g., including the effect of improving aggression) can be demonstrated with other KDM1A inhibitors.

Example 4: Evaluation of the effect of KDM1A inhibitors on social atrophy

While mice have a great deal of power, rats are known to be more sociable. To further characterize the therapeutic effect of KDM1A, such as Compound 1, on the treatment of behavioral changes, the effect of Compound 1 on another type of behavioral change, social atrophy, was evaluated in rats using a rat separation rearing model.

In this model, after weaning on the 21st day of life (PND21), rats were isolated and the normal environment predicated on their social behavior was taken away. Isolation at this stage in the development of rats can lead to behavioral changes, especially lack of interest in social interaction, which can be used as a model for human social atrophy.

4.1 Method

Immediately after weaning (21-24 days postpartum), 48 Spraque-Dawley male rats were divided into two groups: control (non-isolated; n = 12), maintaining 3-4 animals per cage; Containment (n = 36), 1 animal per cage. After birth (PND), starting on day 61, adult isolated male rats were treated with vehicle, 0.16 mg / kg / day Compound 1 or 0.48 mg / kg / day Compound 1 (n = 12 / group) for 5 weeks. Treatment. The route of administration was drinking water and vehicle 1.8% 2-hydroxypropyl-β-cyclodextrin. Drug concentrations were adjusted weekly by body weight and water consumption. During the last week of treatment, all animals were tested for RI (PND94) to assess social behavior and EMP (PND87-88) to assess anxiety behavior the other day.

A resident-intruder (RI) test was performed as follows in a protocol similar to that described for mice in Example 3 above: Briefly, subjects (residents) were tested in their home cage for one week without changing bedding. For a while. On the day of the test (PND94), fairly young and small subjects (invaders; 50-day-old Spraque-Dawley rats) were introduced into the resident home cage. Sessions were video-recorded for 15 minutes, and social interactions (measured parameters: active and passive social interactions, avoidance and time without social interactions) and the aggressive behavior of the subjects were analyzed as visual impairment experimenters on treatment. .

Elevated Plus Maze (EPM) test was performed according to a protocol similar to that described for the mouse of Example 3 above as follows: EPM consisted of four arms connected to the central square and perpendicular to each other, 50 cm from the bottom. The height was maintained. Two of the opposite arms had a high wall (closed arm, 46.5 x 12 x 42 cm) and the other two arms were open (46.5 x 12 x 0.3 cm). Animals were placed facing the closed arms, the movements were video-recorded for 5 minutes and analyzed video-traced using SMART ^® (v2.5.21, PanLab, SLU, Spain).

Statistical analysis: The non- isolated vehicle group and the isolated vehicle group were compared by t-test. Among the isolated groups, other treatments were compared by one-way ANOVA using Dunnet and SNK post-Hoc analysis.

4.2 Results

The RI trials performed did not show the aggressive behavior of rats, and containment did not significantly affect active or passive social interactions. However, as assessed by the time without social interaction (FIG. 3) and the number of avoidances (FIG. 4), the social avoidance parameters increased significantly in vehicle-treated and isolated rats compared to vehicle-treated and non-isolation rats. Did. The time without social interaction in the isolated rats was dose-dependently decreased by treatment with Compound 1, and the significantly increased avoidance count in the isolated rats was normal by treatment with Compound 1 (i.e., at the level of non-isolated rats). Was recovered (see FIGS. 3 and 4).

In the EPM test, no difference was observed between vehicle-treated and quarantined rats and vehicle-treated and non-contained rats. As assessed in EPM, Compound 1 had no significant effect on anxiety or locomotor activity in rats, which had a beneficial effect by Compound 1 on the social avoidance parameters measured in the RI trials, sedating the drug. It is not because of the effect.

In summary, the data and results obtained in Example 4 show that the KDM1A inhibitor Compound 1 is in rats isolated after weaning without causing sedation, by long-term treatment, corrected behavioral changes, especially rats for social avoidance. It is shown to be administered in a well tolerated dose. Thus, Example 4 further supports the discovery that KDM1A inhibitors, especially Compound 1, can be used in the treatment of (non-sedative) agents of behavioral changes including social atrophy.

Using the protocol described in Example 4, the effect of improving behavioral changes (e.g., including the effect of improving social atrophy) can be demonstrated with other KDM1A inhibitors.

Example 5: Evaluation of KDM1A inhibitor effect using three chamber tests (TCT) in mice

KDM1A inhibitor Compound 1 was further tested for social behavior change, three chamber tests (TCT) in additional animal models. TCT is a commonly used method for measuring the social behavior of mice, and can be used to assess the effectiveness of compounds to treat social interaction changes using animals that exhibit innate or acquired defects in social behavior.

In this test, after adapting to the three chamber spaces, mice were released into the middle chamber to explore other compartments. In the adjacent 'mouse' section, while a mild stimulus mouse was placed in a mesh-wire container, in another adjacent section, a similar container was placed without the stimulation mouse (observation section). The tendency to access or avoid compartments with stimulus mice provides a measure of social interaction behavior / sociality. Wild-type mice prefer social interaction and spend more time in the mouse compartment compared to the observation compartment.

5.1 Method

In this study, 8 months old female SAMP8 mice were treated with carrier (n = 9) or 0.96 mg / kg / day of compound 1 (n = 12) for 4 months before TCT. Vehicle (1.8% 2-hydroxypropyl-β-cyclodextrin, Sigma-Aldrich, Spain) or Compound 1 (diluted in carrier) was administered to drinking water. SAMR1 mice treated with the carrier were included as a control (n = 11). Drug concentrations were calculated weekly as a function of body weight and corrected as a function of drinking water consumption.

TCT was performed in a Plexiglas transparent box with three identical continuous chambers (15 x 15 x 20 cm) with two identical small metal cages placed in both side chambers. Adjacent chambers were connected and the animals were able to move freely with each other. Subjects (SAMR1 or SAMP8 female mice) were allowed to explore the device for 5 minutes. This habituation time was monitored to avoid animals preferring one of the chambers. Then, a new female mouse was introduced into one of the metal cages (mouse chamber) and the other cage (observation chamber) was left empty. The time spent in each chamber and the direct search time of new mice were measured for a total observation time of 10 minutes.

Statistical Analysis : The significance of the search differences between new mice of SAMP8 to SAMR1 mice and new mice of SAMP8 treated with Compound 1 to vehicle-treated SAMP8 mice was assessed using the t test. Two-way ANOVA was used to evaluate the importance of chamber preference. ***: p <0.001.

5.2 Results

The results obtained in this test are shown in Tables 5 and 6. As shown in Figure 5, the carrier-treated SAMR1 female mice spent more time in the mouse chamber compared to the observation chamber. In contrast to the control SAMR1 animals, the carrier-treated female SAMP8 mice did not prefer the mouse chamber over the observation chamber (see Figure 5), and also spent less time exploring new mice compared to the SAMR1 mouse (see Figure 6). ) Showed lack of social behavior. Treatment of female SAMP8 mice with KDM1A inhibitor Compound 1 restored both preference for the socialization chamber (mouse chamber) (Figure 5) and time spent exploring new mice in SAMP8 mice to SAMR1 levels (Figure 6). Therefore, Compound 1 completely corrected the social interaction change / social deficiency of SAMP8 mice.

The results obtained in Example 5 can further be used for the treatment of social behavioral changes (non-sedative) such as KDM1A inhibitors such as Compound 1.

Using the protocol described in Example 5, the effect of improving social behavior change can be demonstrated with other KDM1A inhibitors.

All publications, patents and patent applications cited in this specification are hereby incorporated by reference in their entirety.

Publications, patents and patent applications mentioned in this specification are provided for their disclosure only prior to the filing date of the present application. Nothing in this specification should be construed as an admission that they are prior art in this application.

Although the invention has been described in connection with their specific embodiments, the invention may be further refined, and this application is generally intended to cover any adaptations, uses or adaptations of the invention in accordance with the principles of the invention. It will be understood as, and is within the known or customary practice in the art to which this invention pertains, and includes deviations from the present disclosure that may be applied to the key features of the invention as set forth in the preceding claims.

Claims (29)

KDM1A inhibitor for use in the treatment of behavioral changes. A pharmaceutical composition for use in the treatment of behavioral changes, wherein the pharmaceutical composition comprises a KDM1A inhibitor and one or more pharmaceutically acceptable excipients or carriers. The compound or pharmaceutical composition according to claim 1 or 2, wherein the behavioral change is a social behavioral change. The behavioral change is a social atrophy compound of claim 1 or 3 or the pharmaceutical composition of claim 2 or 3. The behavioral change is an aggressive compound of claim 1 or 3 or the pharmaceutical composition of claim 2 or 3. 6. A compound or pharmaceutical composition according to any one of claims 1 or 3 to 5 or 2 to 5, wherein the patient being treated is a human. The method according to any one of claims 1 or 3, or 2 to 6, wherein the KDM1A inhibitor is 5-(((((1R, 2S) -2- (4- (benzyloxy)). Phenyl) cyclopropyl) amino) methyl) -1,3,4-oxadiazol-2-amine, or a pharmaceutically acceptable salt or solvate thereof, or a compound or pharmaceutical composition. The compound or pharmaceutical composition of any one of claims 1 or 3 to 7, or wherein the KDM1A inhibitor or pharmaceutical composition is administered orally. A method of treating behavioral changes in a patient comprising administering to the patient a therapeutically effective amount of a KDM1A inhibitor. 10. The method of claim 9, wherein the behavioral change is a social behavioral change. The method of claim 9 or 10, wherein the behavioral change is social atrophy. 11. The method of claim 9 or 10, wherein the behavior change is aggressive. The method of claim 9, wherein the patient to be treated is a human. The method according to any one of claims 9 to 13, wherein the KDM1A inhibitor is 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1, 3,4-oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof. 15. The method of any one of claims 9-14, wherein the method comprises orally administering a KDM1A inhibitor. Use of a KDM1A inhibitor for the manufacture of a medicament for the treatment of behavioral changes. The use according to claim 16, wherein the behavioral change is a social behavioral change. Use according to claim 16 or 17, wherein the behavioral change is social atrophy. Use according to claim 16 or 17, wherein the behavioral change is aggressive. Use according to any of claims 16 to 19, wherein the patient to be treated is a human. The KDM1A inhibitor according to any one of claims 16 to 20, wherein the KDM1A inhibitor is 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1, 3,4-Oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof. Use according to any of claims 16 to 21, wherein the medicament is for oral administration. Use of KDM1A inhibitors for the treatment of behavioral changes. 24. The use according to claim 23, wherein the behavioral change is a social behavioral change. 25. The use according to claim 23 or 24, wherein the behavioral change is social atrophy. 25. The use according to claim 23 or 24, wherein the behavioral change is aggressive. 27. The use according to any one of claims 23 to 26, wherein the patient to be treated is a human. 28. The method according to any one of claims 23 to 27, wherein the KDM1A inhibitor is 5-(((((1R, 2S) -2- (4- (benzyloxy) phenyl) cyclopropyl) amino) methyl) -1, 3,4-Oxadiazole-2-amine, or a pharmaceutically acceptable salt or solvate thereof. 29. The use according to any one of claims 23 to 28, wherein the KDM1A inhibitor is administered orally.

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